• Renata Belfort, Rachele Berria, John Cornell, and Kenneth Cusi.
• The University of Texas Health Science Center at San Antonio, Diabetes Division, Room 3.380S, 7703 Floyd Curl Drive, San Antonio, Texas 78284-3900, USA.
• J. Clin. Endocrinol. Metab. 2010 Feb 1;95(2):829-36.

ContextFenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood.ObjectiveThe aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS).Design And SettingWe conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center.PatientsWe studied 25 nondiabetic insulin-resistant MetS subjects.Intervention(S)We administered fenofibrate (200 mg/d) and placebo for 12 wk.Main Outcome MeasuresBefore and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry.ResultsSubjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity.ConclusionsIn subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.

34 keywords...

hide…